Submissions for variant NM_005120.3(MED12):c.4022G>A (p.Arg1341Gln)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003596217	SCV003518358	uncertain significance	FG syndrome	2023-08-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2199055). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MED12 protein function. This variant has not been reported in the literature in individuals affected with MED12-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1341 of the MED12 protein (p.Arg1341Gln).
Ambry Genetics	RCV004070837	SCV003602218	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-05-20	criteria provided, single submitter	clinical testing	The c.4022G>A (p.R1341Q) alteration is located in exon 28 (coding exon 28) of the MED12 gene. This alteration results from a G to A substitution at nucleotide position 4022, causing the arginine (R) at amino acid position 1341 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/195918) total alleles studied. The highest observed frequency was 0.006% (1/17806) of South Asian alleles. This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003443134	SCV004170329	uncertain significance	not provided	2023-04-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Molecular Genetics Lab, CHRU Brest	RCV003883207	SCV004697734	uncertain significance	X-linked intellectual disability with marfanoid habitus; FG syndrome 1; Cholestasis-pigmentary retinopathy-cleft palate syndrome; Blepharophimosis - intellectual disability syndrome, MKB type		criteria provided, single submitter	clinical testing